[Leish-l] miltefosine for diffuse leishmaniasis

Sun Jul 10 04:46:40 BRT 2011

Hello Carlos

Interferon-gamma is sold as Actimmune for the treatment of CGD.  It was
while it was in trial for CGD that it was provided free for us in DCL
patients in Brazil.  Of course once it approved by the FDA, the company
wasn’t up for providing it free any more.  My memory is that the dose used
for DCL was higher than that recommended for CGD, but I guess you’d now have
to err on the side of caution and stick within the recommended dose.  I also
think it was given along with standard antimonial treatment.  I’d be
interested to hear what Jackson says about this as I am sure that it was he
who treated the DCL patients – and I think it was John David how managed to
broker the free supply at the time.  My understanding was that it was only
the exorbitant cost that prevented its continued use – and that will
probably be the same now.

Anthony: I know that it didn’t work well for VL, but I remember them being
very excited about it for DCL.  Maybe it wasn’t good in the longer term,
which is why no one has pursued it since.  I don’t think it matters what
therapy you give for DCL it will always be back!  It’s a question of what
holds it at bay for the longest time period I guess.

Cheers all, Jennie

-- 

Jenefer M. Blackwell

UWA Winthrop Professor

Interim Director, Centre for Genetic Epidemiology and Biostatistics

Professor in Genetics and Health

Telethon Institute for Child Health Research

100 Roberts Road, Subiaco, WA 6008; PO Box 855, West Perth, WA 6873

Tel: +61 8 9489 7910; Fax +61 8 9489 7700; Email: jblackwell at ichr.uwa.edu.au

UK contact:   

Affiliated PI and Honorary Senior Scientist

Cambridge Institute for Medical Research

Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge
CB2 0XY, UK

Telephone: +44 1223 762812; Fax: +44 1223 331206; Email: jmb37 at cam.ac.uk

From: leish-l-bounces at lineu.icb.usp.br
[mailto:leish-l-bounces at lineu.icb.usp.br] On Behalf Of Carlos Costa
Sent: 09 July 2011 23:07
To: Leish-L
Cc: Josh Berman; dagobertosilveira at superig.com.br; Dorcas Lamounier Costa;
jurbina at mac.com; Pierre BUFFET; Robert Vinson; Raimunda Sampaio; Shyam
Sundarmail; robertobadaro768 at gmail.com; Mark Nawacki; Fernando Koremblum;
joseanegodinho at yahoo.com.br
Subject: Re: [Leish-l] miltefosine for diffuse leishmaniasis

Dear friends,

This is really a such touching and motivated community, and leish-l is
proving to be an excellent tool for solving the leishmaniasis toughest
problems throughout the world. The word "together" sounds really powerful in
such a cases.

What os showing up from these kind emails is a face of science coming not
only from the bench, the hospitals, the field, but a science coming straight
from the heart.

Let me summarize some of the lessons and suggestions. Please correct me if I
skip some.

1) Hot bath - Teresina is very hot, and hot showers are rare here. However,
we can easily provide her an electric shower. Should it be a tube? How long
the bath would last?

2) BCG - one or two shots.  We will do it. Any hint about the intervals
between the shots?

3) Previous drug therapy: ImunoglucanTM (cell wall of Saccharomyces
cerevisiae), and saquinavir, after her delivery (Intracellular survival of
Leishmania species that cause visceral leishmaniasis is significantly
reduced by HIV-1 protease inhibitors.
<http://www.ncbi.nlm.nih.gov/pubmed/18816190> ).

4) Besides miltefosine we got a good hint where to find it (Paladino,
Canada), which has excellent temporary effect (Zerpa et al, 2006), we should
consider: 

a) lower/corrected doses of paramomycin (Bryceson) - we have also to find
the drug outside Brazil, since it is not distributed/approved here; 

b) gamma-interferon (who produces/sells it?).

c) fluconazol/itraconazol/(voriconazol?).

d) amiodarone - in vitro testing does not sounds so good.

e) topic imiquimod  (IxiumTM cream) - apparently easy to find. concentration
of 5%?

f) photodynamic therapy - with Dr. Dagoberto Silveira, we are investigating
where to do it around.

g) immunotherapy with suicide photo-inactivated Leishmania (KP Chang).

Please check what really seems reasonable. My feeling is that most of the
suggestions can be tried.

My warmest regards,

Carlos.

2011/7/8 Pierre BUFFET <pierre.buffet at upmc.fr>

Anthony,

because there are only a few options left, would you consider at one point
low dose pentamidine (3 mg/kg every week or so, as you did in DCL patinets
in Ethiopia in the 70s if I remember)? Could be used either to stabilize the
situation before starting on a coadministration, or as a maintenance after
the co-administration, in both cases with careful monitoring of kidney
function ?

Pierre

 Anthony Bryceson <a.bryceson at doctors.org.uk> a écrit :

Dear Carlos
As you are well aware DCL is very difficult to treat. The big problem is
that the defect in specific CMI is more profound than that in VL and may
never recover, in contrast with the defect in VL which bounces back quickly.

To have any chance of curing the patient, treatment  should be monitored by
quantitative slit skin smears (as for splenic aspirates in VL) from multiple
pre-selected sites, every week or two weeks, and treatment continued until
negativity and for some weeks or months longer.  When slit skin smears
become negative, hunt for any nodular or infiltrated lesions and take deep
biopsies and look for amastigotes there. Keep on hunting and smearing.
Sometimes, at the end of all this, evidence of CMI may appear, and cure
becomes a possibility. I am sure that the method of treating is more
important than the choice of drug - so long of course that the parasite is
susceptible to the drug.

Hannah Akuffo has sent you the abstract relating to 3 patients treated by
Sabawork Teklemariam in Addis Abeba. That article details this approach.

Do you know the species of Leishmania causing Maria's DCL, and its
sensitivities? In Addis Abeba parasites were cultured from two of the
patients and sensitivities determined and isobolograms drawn to look for
synergy. The isolates were sensitive to paromomycin and sodium
stibogluconate was synergistic. It would be worth while to make cultures
before you start any new treatment and have the isolate tested in this way.
I expect that you have a lab that could do this; if not, Simon Croft might
be able to advise.

Miltefosine has been very successful in a number of situations in South
American CL and showed promise for DCL,  but patients relapsed despite
prolonged treatment.
1. Zerpa O, Ulrich M, Blanco B, et al. Diffuse cutaneous leishmaniasis
responds to miltefosine but then relapses. Br J Dermatol.
2007;156:1328-1335.

In a few patients with VL-HIV confection whom I treated in London,
miltefosine worked well at first, but the patients relpased while still on
treatment and drug resistance was supected but not tested. Miltefosine has a
pharmacokinetic profile with a long tail that might make it susceptible to
the devlopment of resistance, especially if the therapeutic window for a
given isolate was narrow. So you might want to think about adding a second
drug to go with miltefosine from the beginning. I am not sure what might be
the best drug for combination; perhaps Josh Berman might have an opinion. It
is of course essential to ensure contraception.

You could also consider the combination of paromomycin and low dose SSG. In
view of Maria's poor renal function you might need to modify the dose of
paromomycin and to monitor function.

Robert Vinson is CEO of Paladin Labs, and would I am sure help you locate
miltefosine. <rvinson at paladin-labs.com>

Richard Chin is CEO of One World Health,  and would, I am equally sure, help
you locate paromomycin, should you consider that path.
http://www.oneworldhealth.org/contact-us  Phone: +1 415-421-4700 Fax: +1
415-421-4747

I wish you and Maria all the best in this venture.
Anthony

Dear Jennie
Immunotherapy proved rather disappointing in VL. It seems that the patient
needs a decent immune response in the first place to benefit from
immuno-boosting.
Sadly
Anthony

On 6 Jul 2011, at 20:04, Carlos Costa wrote:

Dear all,

Maria Cleudimar has cutaneous diffuse leishmaniasis due to Leishmania
amazonensis. She used to be a long time patient form Dr. Jackson Costa, in
the countryside of Maranhão State, Brazil, since she was 10 years old, after
a disease that started when she was just five. Now, she is under my and
Dorcas care, at the age of 30, living in the city of Teresina.

Her long time DCL does not respond to the treatment antimonium anymore.
Although we still prescribe liposomal amphotericin B at very low dose
(3mg/kg/once a week), her situation is deteriorating progressively, her
renal function does not allow any additional dosing since creatinine is
presently above 3mg/dL, and previous biopsy had shown tubular damage
apparently secondary to the drug, without evidence of amyloidosis. We tried
several combinations of different drugs, without success. Her situation
worsened a lot during her recent pregnancy (the baby is eight months old
now).

Our hope now stands only in miltefosine, for oral chronic use, but the drug
is not licensed or available in Brazil yet (to my knowledge).

With her permission I attached some of her pictures, hoping to sensitize
critical people in order to help me to get miltefosine and the permission
for prescription in Brazil (or any other oral drug with promising efficacy,
and without nephrotoxicity, if known). Moreover, we need to know about the
dose adjustment for the renal impairment, and how long the drug could safely
be used.

One picture shows her face before treatment, and another after the
pregnancy, with the baby. One shows the situation of her thighs, another the
calf of the leg and the last one the infiltration of the palate.

Hoping a little from friends, my kindest regards,

Carlos.

PS. Please understand that the pictures are allowed not for publication or
public presentation. Cleudimar permission is restricted to this forum.

--
Carlos H. N. Costa, MD, DSc.
President
Sociedade Brasileira de Medicina Tropical
(Brazilian Society of Tropical Medicine)
Instituto de Doenças Tropicais Natan Portella
Universidade Federal do Piauí
Rua Artur de Vasconcelos 151-Sul
64049-750 Teresina-PI
Brazil
Telephones: +55 86 3221-3413 (work); +55 86 8838-3303 (mobile).

Aviso: As informações contidas nesta mensagem são CONFIDENCIAIS, protegidas
pelo sigilo legal, por direitos autorais e destinadas exclusivamente à
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Warning: This message is meant only for the intended recipient of the
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<cleu antes grav 13jan09.jpg><cleu e nene.jpg><cleu santada
recorte.jpg><cleu panturrilhas.jpg><cleu
palato.jpg>_______________________________________________
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Leish-l at lineu.icb.usp.br
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-- 
Carlos H. N. Costa, MD, DSc.

President

Sociedade Brasileira de Medicina Tropical 

(Brazilian Society of Tropical Medicine)

Instituto de Doenças Tropicais Natan Portella
Universidade Federal do Piauí

Rua Artur de Vasconcelos 151-Sul

64049-750 Teresina-PI
Brazil
Telephones: +55 86 3221-3413 (work); +55 86 8838-3303 (mobile).

Aviso: As informações contidas nesta mensagem são CONFIDENCIAIS, protegidas
pelo sigilo legal, por direitos autorais e destinadas exclusivamente à
pessoa ou organização para a qual a mensagem foi destinada.
Warning: This message is meant only for the intended recipient of the
transmission.  It is forbidden any unauthorized use, alteration,
reproduction and distribution. If you are not the correct recipient, please
notify us immediately by return e-mail and delete this message from your
system. 

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